Reduction of development timeline, costs and uncertainty are advantages of DR over de novo new molecular entity (NME) drug discovery. Since preclinical safey, manufacturing, and first-use in humans data are available, these steps of drug development are skipped. DR, however, still requires clinical trials to demonstrate that the drug, at a dose regimen, is effective and safe for a new therapeutic indication. These studies should preferably be randomized controlled trials (RCT), including a control group receiving placebo or active comparators, concealment of allocation, masking, intention-to-treat analysis, sufficiently large sample size, and assessments of reliable and valid clinical outcomes.

DR is a logical option when scientists tackle the challenge of finding effective and safe medications for emerging viral infections that spread with fast-rising death tolls. In the quest for life-saving therapies, time is certainly the most valuable asset. Investigators hear the clock ticking constantly to remind them the inexorable pace of the pandemics and its consequences. Nonetheless, although skipping steps, DR still takes time and success cannot be taken for granted.

Over 80 trials are underway to investigate whether a variety of drugs, mostly antivirals and antimalarials, could be useful to treat COVID-19 66. Rosa SGV, Santos WC. Clinical trials on drug repositioning for COVID-19 treatment. Rev Panam Salud Pública 2020; 44:e40.,77. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA 2020; [Epub ahead of print].. Most trials search for drugs that could alleviate the COVID-19 acute respiratory distress syndrome (ARDS) and decrease its fatality rate. A few trials were designed to find out drugs useful in proactive prophylaxis and/or to prevent COVID-19 progression from oligosymptomatic infections to severe ARDS. These goals may entail distinct modes of action and dosage regimens. Benefit-risk balance also depends on the pursued clinical goal. Drugs useful to treat ARDS are not necessarily those suitable for prophylaxis and preventive interventions.

Chloroquine (CQ), an antimalarial 4-aminoquinoline and its derivative hydroxychloroquine (HCQ), are the most notorius drugs under investigation for COVID-19.

Furthermore, a problem for using CQ and/or HCQ for prophylaxis or prevention of ARDS in patients at risk of severe disease is their narrow margin of safety. Depending on daily doses, length of use and cumulative doses both antimalarial drugs may cause retinopathy and irreversible vision loss 1515. Haladyj E, Sikora M, Felis-Giemza A, Olesinska M. Antimalarials - are they effective and safe in rheumatic diseases? Reumatologia 2018; 56:164-73.. Overdosing and/or prolonged use of CQ/HCQ was reported to cause heart conduction disorders, low blood pressure, cardiomyopathy, cardiac arrest and death 1616. Roos JM, Aubry MC, Edwards WD. Chloroquine cardiotoxicity: clinicopathologic features in three patients and comparison with three patients with Fabry disease. Cardiovasc Pathol 2002; 11:277-83.. CQ and HCQ also cause nausea and vomiting, loss of appetite, unpleasant metallic taste, headache, blurred vision, itching, abdominal cramps, diarrhea, tinnitus and hearing deficits, shortness of breath, weakness and mental disturbances 1515. Haladyj E, Sikora M, Felis-Giemza A, Olesinska M. Antimalarials - are they effective and safe in rheumatic diseases? Reumatologia 2018; 56:164-73.. This constellation of side effects discourages the use of CQ/HCQ for prophylaxis or in less severe cases of COVID-19. When prescribing CQ-HCQ for patients at elevated risk of developing ARDS, physicians should be aware that this subpopulation of patients overlaps with that at higher risk for life-threatening drug adverse events. As with any drug, risks and potential benefits of CQ-HCQ must be properly balanced. An insurmountable obstacle for weighing risks against benefits, however, is the fact that CQ-HCQ’s efficacy for COVID-19 remains unproven so far.

A search (April 16, 2020) on the U.S. National Institutes of Health clinical trial registry (http://www.ClinicalTrials.gov) identified 16 studies (recruting, active, suspended, terminated or completed) about HCQ or CQ. Eight studies were trials of CQ or HCQ for COVID-19, while the remaining ones were for other indications. Five trials of HCQ/CQ for COVID-19 were open-label studies (no masking), while one RCT is double-blinded (participant, investigator) and two RCTs are quadruple-blinded (participant, care provider, investigator, outcomes assessor) RCTs.

Open label trials entail a high risk of bias and, under the current scenario of pandemics, many investigators may have expectations about the outcome. One is a single-arm study while another open-label trial was designed to evaluate whether HCQ plus azithromycin (a drug for bacterial infections) is superior to HCQ monotherapy. Suffering from important methodological limitations, the open-label trials will not be sufficient to clarify whether CQ and HCQ are in fact useful to treat COVID-19-ARDS. The most robust evidence along this line is expected to come from three RCTs the design of which involves masking and concealment of allocation. These RCTs are scheduled to be completed in September 2020, April 2021 and February 2022.

Concluding, it is worth reminding those who are desperately seeking a remedy for the pandemics a powerful Shakespearean metaphor: “All that glitters is not gold - You’ve often heard that said. Many men have sold their souls; Just to view my shiny surface. But gilded tombs contain worms” (William Shakespeare; The Merchant of Venice, Act II, Scene VII, adapted to modern English).

Contributors

F. J. R. Paumgartten contributed to the design and writing of the first version of the manuscript. I. F. Delgado participated in the preparation and review of the manuscript. L. R. Pitta and A. C. A. X. Oliveira collaborated in the writing, bibliographic survey and revision of the manuscript.